Role of oxidative stress in nickel chloride-induced cell injury in rat renal cortical slices

Abstract

Nickel chloride (NiCl 2) induced lactate dehydrogenase (LDH) release and lipid peroxidation (LPO) in rat renal cortical slices in vitro in a concentration- (0–2 mM) and time- (0–4 hr) dependent manner, with initial significant LDH release occurring as early as 1 hr, whereas significant increase in LPO started 3 hr after exposure, suggesting that LPO results from renal cell injury. Both NiCl 2-induced LDH release and LPO were prevented significantly by glutathione and dithiothreitol, suggesting that NiCl 2-induced renal cell injury is dependent on thiols. However, such injury is not dependent solely on thiols, because (a) these thiols failed to inhibit completely the uptake of Ni 2+ by the renal cortex, and (b) diethylmaleate pretreatment failed to increase NiCl 2-induced cell injury further. Superoxide dismutase partially reduced the NiCl 2-induced LDH release without affecting LPO and glutathione, whereas catalase did not affect such LDH release and LPO. Dimethylthiourea and DMSO completely prevented NiCl 2-induced LPO, but only partially reduced LDH release. Deferoxamine prevented NiCl 2-induced renal cell injury without affecting LPO and without significantly reducing Ni 2+ uptake by the renal cortex, suggesting that nickel chelation is not important in such prevention of injury. NiCl 2-induced inhibition of para-aminohippurate uptake was prevented significantly by thiols, deferoxamine, and dimethylthiourea. NiCl 2-induced loss of cellular glutathione content was prevented significantly by thiols and deferoxamine, but not by superoxide dismutase and dimethylthiourea. These results suggest that LPO was not related to NiCl 2-induced lethal renal cell injury, whereas such injury may be caused by the induction of the Fenton reaction, generating hydroxyl radicals.